Submissions for variant NM_015681.6(B9D1):c.151T>C (p.Ser51Pro)

gnomAD frequency: 0.00011  dbSNP: rs546359789

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821741	SCV000962510	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 51 of the B9D1 protein (p.Ser51Pro). This variant is present in population databases (rs546359789, gnomAD 0.01%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 25920555, 26477546; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 663790). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265575	SCV001443739	likely pathogenic	Joubert syndrome 27	2020-01-27	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change in patients with Joubert Syndrome (PMID: 26477546, 25920555). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (14/282748) and thus is presumed to be rare. The c.151T>C (p.Ser51Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.151T>C (p.Ser51Pro) variant is classified as Likely Pathogenic.
GeneDx	RCV001759613	SCV001987714	uncertain significance	not provided	2021-03-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified independently and in conjunction with additional variants in individuals with features of Joubert syndrome in published literature (Srour et al., 2015; Kroes et al., 2015; Zwaveling-Soonawala et al., 2018); This variant is associated with the following publications: (PMID: 25920555, 26477546, 29165578)
CeGaT Center for Human Genetics Tuebingen	RCV001759613	SCV004142444	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	B9D1: PM2, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586950	SCV005076791	uncertain significance	not specified	2024-04-10	criteria provided, single submitter	clinical testing	Variant summary: B9D1 c.151T>C (p.Ser51Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251378 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in B9D1 causing Joubert Syndrome And Related Disorders (4.8e-05 vs 0.0004), allowing no conclusion about variant significance. c.151T>C has been reported in the literature in individuals affected with Joubert Syndrome (Srour_2015, Kroes_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26477546, 25920555, 29165578). ClinVar contains an entry for this variant (Variation ID: 663790). Based on the evidence outlined above, the variant was classified as uncertain significance.